Thesis topic proposal
Effects of complement C5a inhibitor therapy on macro- and microcirculatory disturbances in experimental models of non-occlusive mesenteric ischemia


Institute: University of Szeged
theoretical medicine
Doctoral School of Multidisciplinary Medical Scienses

Thesis supervisor: Gabriella Varga
Location of studies (in Hungarian): SZTE ÁOK Sebészeti Műtéttani Intézet
Abbreviation of location of studies: SMI

Description of the research topic:

The non-occlusive mesenteric ischemia (NOMI) develops in the presence of intact mesenteric arteries and without their physical occlusion. Nevertheless, the process can lead to severe circulatory disturbances, affecting large proportion of the splanchnic area. Early diagnosis is difficult, because of the lack of specific signs. At the early phase of NOMI usually there are no other significant symptoms besides some diffuse abdominal pain, which results in an uncertain early diagnosis. Nonetheless, abdominal distension, leukocytosis and hypotension may occur, but those can be absent in more than 50% of the cases. The launch of an early, targeted therapy is inevitable which contributed to a significant decrease of the mortality in the recent decades, although it is still excessively high, it is around 50 % nowadays, therefore attempts to further decrease should be done. There is only a few data available about the pathogenesis of NOMI, though it can be assumed that long lasting and explicit vasoconstriction is accompanied by severe mucosal damage of the small intestines. Therefore, according to the present knowledge, in case of the diagnosis of NOMI vasodilator therapy should be started immediately, including intraarterial administration of papaverin and prostaglandin.
In our experiments the role of complement C5a in the pathophysiology of NOMI is investigated. A synthetic, antisense peptide is administered as selective C5a inhibitor in a large animal (swine)- and a rat model of NOMI.

Study I: The C5a complement factor has a central role in the development of hemodynamic alterations after cardiogenic shock. The C5a is produced by enzymatic cleavage during the activation of the complement system and it is able to contribute to the inflammatory process, like chemotactic activity, induction of histamine release from mast cells, activation of cyclooxigenase and lipoxigenase enzymes.
The experiments are performed on Vietnamese minipigs. The effects of C5a inhibitor treatment on the inflammatory complications are examined in an experimental model of cardiac tamponade. Following the cardiac tamponade, the gastrointestinal microcirculation is highly impaired because of the vasoconstriction of the splanchnic area. By the administration of C5a inhibitor, the circulatory disturbances can be reduced or ceased.
StudyII-III: The experiments are performed on male Sprague-Dawley rats. The short (less than 3 hours)- and long term (over 24 hours) inflammatory complications of NOMI are investigated in a rat model of partial aortic occlusion, induced by partial clamping of the proximal, abdominal aorta. The C5a inhibitor treatment influences the inflammatory, micro- and macrohemodynamic consequences of NOMI that refers to the significance of the complement activation during the microcirculatory disturbances, caused by the mesenteric hypoperfusion. The macro- and microhemdynamic alterations and the consecutive inflammatory process finally result micro- and macroscopic epithelial damage in the small intestine.

Required language skills: English
Number of students who can be accepted: 1

Deadline for application: 2019-08-31

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